5 controversial drugs approved by the FDA

Garnering FDA approval of a new drug is an arduous process that can take several years. Of the many novel drugs that go through this process, few actually get approved. 

“Most drugs that undergo preclinical (animal) testing never even make it to human testing and review,” notes the FDA. “The drugs that do must undergo the agency's rigorous evaluation process, which scrutinizes everything about the drug—from the design of clinical trials to the severity of side effects to the conditions under which the drug is manufactured.”

But no process is perfect, and safety concerns about drugs often arise only after they’ve been approved. For instance, of the 222 drugs OK’d by the FDA from 2001 through 2010, 71 of them—nearly one-third—had significant safety issues after coming to market, researchers found. 

Because it’s an issue worth examining, let’s look at five controversial but FDA-approved drugs. Some have been withdrawn from the market, while others are still being prescribed.  

Mibefradil (Posicor)

At the time of its introduction in 1997, mibefradil was a new type of blood-pressure medication, which was also prescribed for angina. Mibefradil blocks both T- and L-type calcium channels, with a greater affinity for T-type. 

When used, mibefradil slightly decreased heart rate but didn’t cause reflex tachycardia. It also inhibited cytochrome P450 liver enzymes and could increase blood concentrations of drugs used in conjunction. Its interaction with drugs that impact liver metabolism caused breakdown of abdominal muscles in a handful of individuals, which was very scary at the time.

In 1998, Roche withdrew mibefradil from the market following a spate of dangerous/lethal interactions when used along with 25 other drugs—including some that are remarkably common, such as antibiotics and antihistamines.

Mibefradil was taken by about 200,000 Americans and almost double that worldwide. “Its withdrawal was a logistical nightmare for many large cardiology practices faced with the need to notify patients that they would need to obtain a different prescription,” according to the authors of an article published in Circulation. “In light of other recent withdrawals of medications from the market, the Posicor situation presented new questions about the perceived haste of the [FDA] to approve new medicines, a politically mandated speed-up that has drawn both praise and criticism.”

Propoxyphene (Darvon, Darvocet)

Propoxyphene was introduced in the United States in 1957, and its presence on the market caused a maelstrom of controversy for decades. This weak opioid was rolled out widely, but it was soon noted to cause cardiotoxicity, arrhythmias, and seizures. It also interfered with drug metabolism by cytochrome P450. 

But propoxyphene was only as potent as acetaminophen or aspirin, which raised questions as to why it was prescribed in the first place. Propoxyphene was even combined with acetaminophen, which was sold as Darvocet. Moreover, propoxyphene’s euphoria-inducing properties made it a potential drug of abuse. This drug turned out to be especially dangerous in the elderly. Overall, between 1981 and 1999, more than 2,110 propoxyphene-related deaths were reported.

“The use of this agent is highly discouraged,” wrote the authors of a review in the American Journal of Therapeutics published as recently as 2006. “The toxicity of this drug is partially related to norpropoxyphene, a non-opioid cardiotoxic metabolite. The mere warnings of fatalities within the package insert should alert any cautious prescriber on the dangers of this agent and dampen its prescribing potential.”

Despite being introduced more than 50 years prior, it wasn’t until 2010 that the FDA made a strong statement on the danger of this drug. 

“The U.S. Food and Drug Administration is recommending against continued prescribing and use of the pain reliever propoxyphene because new data show that the drug can cause serious toxicity to the heart, even when used at therapeutic doses,” the FDA cautioned.

The FDA recommendation was based on data from a study in which researchers demonstrated that increasing doses of propoxyphene were detrimental to the heart.

“The results of the new study showed that when propoxyphene was taken at therapeutic doses, there were significant changes to the electrical activity of the heart: prolonged PR interval, widened QRS complex and prolonged QT interval. These changes, which can be seen on an electrocardiogram, can increase the risk for serious abnormal heart rhythms. FDA has concluded that the safety risks of propoxyphene outweigh its benefits for pain relief at recommended doses,” the agency stated.

In response to these findings, the manufacturer subsequently withdrew the drug from the market in 2010.

Pimavanserin (Nuplazid)

Pimavanserin is an atypical antipsychotic. Like other antipsychotics, it has a boxed warning about heightened mortality risk in older patients with dementia-related psychosis. Of note, this drug is used to treat Parkinson disease psychosis, which is marked by hallucinations and delusions. Even though antipsychotics can be dangerous, media and public reports focused on pimavanserin as having a particularly high risk of death.

In light of these concerns, the FDA conducted a robust analysis of all extant data and released their results in 2018, saying that they didn’t identify any new or unexpected safety findings.

“In assessing the reports of deaths, FDA considered that patients with Parkinson’s disease psychosis, for whom Nuplazid is indicated, have a higher mortality (death) rate due to their older age, advanced Parkinson’s disease, and other medical conditions,” the agency wrote. “Moreover, Nuplazid is primarily distributed through a patient support program and a specialty pharmacy network, which increases the likelihood that deaths will be reported to the manufacturer.”

Nevertheless, the FDA did notice some highly concerning prescribing patterns with respect to pimavanserin, including its concomitant prescription with other antipsychotics known to cause QT prolongation. The FDA stressed that only pimavanserin was approved for the treatment of Parkinson disease psychosis. 

Diethylstilbestrol

Diethylstilbestrol (DES) was a synthetic estrogen first formulated in 1938. DES was prescribed between 1938 and 1971 by US physicians to pregnant women to prevent miscarriages and for other pregnancy issues, such as premature birth. In 1953, researchers demonstrated that this drug did not prevent such problems. But, it was still available for prescription until 1971, when the FDA warned that DES caused clear cell adenocarcinoma, a rare type of vaginal cancer, in girls and young women exposed in utero. Because there wasno test for DES exposure, cohorts of girls had to be screened for cancer. 

Eteplirsen

In 2016, the FDA approved eteplirsen, an injection and the first drug approved for the treatment of Duchenne muscular dystrophy (DMD). Specifically, it is indicated for patients with a mutation of the dystrophin gene susceptible to exon 51 skipping, which affects approximately 13% of the DMD population. 

Despite concerns raised by FDA stakeholders about insufficient, low-powered research, the drug was approved. 

According to an FDA memo from Ellis F. Unger, MD, director, Office of Drug Evaluation, “[T]he applicant [drug manufacturer Sarepta Therapeutics] has not provided substantial evidence of effectiveness from adequate and well controlled trials to support conventional approval. I also agree that the applicant has not provided support for accelerated approval, i.e., evidence from adequate and well controlled trials of an effect on a biomarker that is reasonably likely to predict effectiveness.” 

If interested, the saga surrounding this drug is documented by the consumer rights advocacy group Public Citizen.